title: Mitotane reduces human and mouse ACTH-secreting pituitary cell viability and function.
abstract: Medical therapy for Cushing's disease (CD) is currently based on agents mainly targeting adrenocortical function. Lately, pituitary-directed drugs have been developed, with limited efficacy. Mitotane, a potent adrenolytic drug, has been recently investigated for the treatment of CD, but the direct pituitary effects have not been clarified so far. The aim of our study was to investigate whether mitotane may affect corticotroph function and cell survival in the mouse pituitary cell line AtT20/D16v-F2 and in the primary cultures of human ACTH-secreting pituitary adenomas, as an in vitro model of pituitary corticotrophs. We found that in the AtT20/D16v-F2 cell line and in primary cultures, mitotane reduces cell viability by inducing caspase-mediated apoptosis and reduces ACTH secretion. In the AtT20/D16v-F2 cell line, mitotane reduces Pomc expression and blocks the stimulatory effects of corticotropin-releasing hormone on cell viability, ACTH secretion, and Pomc expression. These effects were apparent at mitotane doses greater than those usually necessary for reducing cortisol secretion in Cushing's syndrome, but still in the therapeutic window for adrenocortical carcinoma treatment. In conclusion, our results demonstrate that mitotane affects cell viability and function of human and mouse ACTH-secreting pituitary adenoma cells. These data indicate that mitotane could have direct pituitary effects on corticotroph cells.
authors.affiliation: Section of Endocrinology, Department of Medical Sciences, University of Ferrara, Via Savonarola 9, 44100 Ferrara, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Gentilin
authors.forename: Federico
authors.initials: F
authors.lastname: Tagliati
authors.forename: Massimo
authors.initials: M
authors.lastname: Terzolo
authors.forename: Matteo
authors.initials: M
authors.lastname: Zoli
authors.forename: Marcello
authors.initials: M
authors.lastname: Lapparelli
authors.forename: Mariella
authors.initials: M
authors.lastname: Minoia
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Ambrosio
authors.forename: Ettore C
authors.initials: EC
authors.lastname: Degli Uberti
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Zatelli
mesh_terms: D049913:ACTH-Secreting Pituitary Adenoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D052680:Corticotrophs / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008939:Mitotane / Q000494:pharmacology*; D047748:Pituitary ACTH Hypersecretion / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism
chemical_list: D011333:Pro-Opiomelanocortin; D008939:Mitotane; D000324:Adrenocorticotropic Hormone
keywords: Cushing's disease; POMC; corticotropin-releasing hormone; mitotane; pituitary function